Altered structural integrity of cortical synapses has been demonstrated in a variety of forms of mental retardation, including those attributable to chromosomal abnormalities (e.g., Down Syndrome, Fragile X, Angelman Syndrome, Praeder-Willi Syndrome, William's Syndrome), prenatal exposure to teratogens (e.g., ethanol) and severe neonatal seizures. Most of these structural defects are at synapses located on dendritic spines, sites of glutamatergic input, and they can occur in humans and animal models. The efficiency, distribution, and structure of these glutamatergic cortical synapses undergo substantial modulation by experience, neural activity, and other neurotransmitters such as serotonin during normal development. (Interference with normal glutamatergic synaptic transmission can lead to seizures, neurotoxicity, and development of abnormal cortical architecture). This program project is a multi-faceted inquiry into (1) the initial molecular assembly of the cortical glutamate synapse (Project I); (2) its capacity for transferring behaviorally relevant signals during development (Project II); and (3) its modulating during postnatal development by (i) two neighboring cell types-subcortical white matter neurons and astrocytes, (ii) the modulators, serotonin (5-HT) and nitric oxide, and (iii) the 5-HT and glutamate neurotransmitter transporters (Projects III, IV, and V). A Developmental Neurobiology Imaging Core (Core B) and an Administration/Project Development Core (Core A) Neurobiology Imaging Core (Core B) and an Administration/Project Development Core (Core A) will provide critical services and will promote synergy among projects. By learning the molecular components of these synapses, their functional properties in a physiological context, and the mechanisms of their modification by intrinsic gating pathway in the normal neonate, this project will provide a substantial new basis for understanding the sensitivity of developing glutamate synapses to the convergent processes that compromise synaptic structure and function in MR.